Is TOE1 p.Val240Met (c.718G>A) pathogenic?

TOE1 p.Val240Met (c.718G>A) is classified Uncertain significance in TOE1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-01-27). AlphaMissense: likely benign (0.0994); Ultra-rare (popmax 0.0534%, afr); Associated with Inborn genetic diseases.

What condition is associated with TOE1 p.Val240Met (c.718G>A)?

TOE1 p.Val240Met (c.718G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TOE1 p.Val240Met (c.718G>A) in the general population?

TOE1 p.Val240Met (c.718G>A) is ultra-rare (popmax 0.0534%, afr) (gnomAD).

What do computational predictors say about TOE1 p.Val240Met (c.718G>A)?

AlphaMissense predicts likely benign (score 0.0994) — an in-silico prediction, not a clinical call.

TOE1 p.Val240Met

c.718G>A · rs137896624 · VCV2155133

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0534%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0994	likely benign
REVEL	0.018	moderately benign-leaning
SaProt	LLR -4.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -1.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 3,446 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	17.58	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0534% African / African-American · 40/74,890 alleles

Filtering AF 0.0402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00719% 116/1,613,928 alleles · ultra-rare exomes 82/1,461,816 · genomes 34/152,112 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0534%	1,872
Admixed American	0.0167%	6,000
Remaining individualsnot grpmax-eligible	0.0096%	10,414
European (non-Finnish)	0.00508%	19,667

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: TOE1
Protein: p.Val240Met
Coding: c.718G>A
MANE Select: NM_025077
dbSNP: rs137896624
Type: single nucleotide variant
Location: chr1:45342609 (GRCh38)
Gene constraint: LOEUF 1.225 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 1 PDB
Residue 240: a UniProt-annotated variant site (in pch7)

Full TOE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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TOE1 p.Arg293His Uncertain significance ★★ ⚠ same condition
TOE1 p.Arg494His Uncertain significance ★★ ⚠ same condition
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TOE1 p.Pro366Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/toe1-p-val240met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown